Dopamine plays a critical role in information processing, with the dorsolateral prefrontal cortex (DLPFC) representing a key node in which normal dopamine function is crucial for normal cognition. Preclinical studies have shown that optimum levels of dopamine signaling in the DLPFC are necessary for optimum cognitive performance. In schizophrenia, impairments exist in cognition and these impairments repeatedly correlate with abnormal DLPFC activity measured with functional imaging techniques such as fMRI. Although indirect evidence supports the hypothesis that decreased DLPFC dopamine transmission is responsible for both the cognitive impairments and the abnormal DLPFC activity in schizophrenia, this hypothesis has yet to be tested in a clinical population. Moreover, a deficit in DLPFC dopamine function in schizophrenia may impact subcortical dopamine function. An abundant literature suggests that prefrontal dopamine activity exerts an inhibitory influence on subcortical dopamine activity. From these observations, it has been proposed that, in schizophrenia a deficiency in cortical dopamine function might translate into disinhibition of subcortical dopamine activity; again, a hypothesis not yet tested in a clinical population. Thus, the current view of dopamine function in schizophrenia proposes that: mesolimbic dopamine projections from the midbrain to subcortical structures might be hyperactive and contribute to the positive symptoms of the illness while hypoactive mesocortical dopamine projections contribute to the cognitive impairments observed in schizophrenia and that this dopamine imbalance might be related, inasmuch as a deficiency in cortical dopamine function might translate into disinhibition of subcortical dopamine activity. In this application we propose to investigate both arms of this hypothesis, in the same subjects, using positron emission tomography (PET) imaging to measure dopamine transmission in the DLPFC as well as the striatum. Subjects will also participate in cognitive testing. If successful, the studies outlined in this application will provide a complete examination of the current dopamine hypothesis of schizophrenia by assessing presynaptic dopamine function (amphetamine-induced dopamine release) in both the DLPFC and striatal subregions. Performing these studies in the same individuals will provide a unique dataset in which the relationship between cortical and subcortical dopamine transmission can be examined. Furthermore, performing cognitive testing in these same subjects will allow us to explore the relationship between DLPFC dopamine transmission and cognition. Improvements in the understanding of this relationship will advance the development of novel treatments for the cognitive impairments in schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia ranks among the top diseases as a cause of disability in industrialized nations and, with onset in adolescence or early adulthood and the lack of fully effective treatments, contributes greatly to the global burden of disease. Impairment in cognitive function represents a key clinical hallmark of schizophrenia, for which there is no clearly effective treatment. In this proposal we seek to better understand the neurobiology underlying the cognitive abnormalities in schizophrenia; with the hope that, in turn, this will advance the development of novel treatments for these cognitive impairments.